G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian...

Epigenetic evolution is a common mechanism used by cancer cells to evade the therapeutic effects of drug treatment. In ovarian cancers, epigenetically driven resistance is thought to be responsible for many late-stage patient deaths. DNA secondary structures called G-quadruplexes (G4s) are emerging as potential epigenetic marks of relevance to cancer evolution, but their prevalence and distribution in ovarian cancer models have never been investigated before.

Here, we describe the first investigation of the role of G4s in the epigenetic regulation of drug-resistant ovarian cancer cells. Through genome-wide mapping of G4s in paired drug-sensitive and drug-resistant cell lines, we find that increased G4 accumulation is associated with enhanced transcription of signalling pathways previously established to promote drug-resistant states, including genes involved in the epithelial to mesenchymal transition and WNT signalling. In contrast to previous studies, the expression-enhancing effects of G4s are not found at gene promoters, but intergenic and intronic regions, indicating that G4s can promote long-range transcriptional regulation in drug-resistant cells. Furthermore, we discover that clusters of G4s (super-G4s) are associated with particularly high levels of transcriptional enhancement that surpass the effects of super-enhancers, which act as well-established regulatory sites in many cancers. Finally, we demonstrate that targeting G4s with small molecules results in significant downregulation of pathways associated with drug resistance, resulting in resensitization of resistant cells to chemotherapy agents.

These findings indicate that G4 structures are critical for the epigenetic regulatory networks of drug-resistant cells and represent a promising target to treat drug-tolerant ovarian cancer.